Effect of polygenic load on striatal dopaminergic deterioration in Parkinson disease

Myung Jun Lee, Kyoungjune Pak, Jong Hun Kim, Yun Joong Kim, Jeehee Yoon, Jinwoo Lee, Chul Hyoung Lyoo, Hyung Jun Park, Jae Hyeok Lee, Na Yeon Jung

Research output: Contribution to journalArticlepeer-review

Abstract

ObjectiveTo investigate the effect of polygenic load on the progression of striatal dopaminergic dysfunction in patients with Parkinson disease (PD).MethodsUsing data from 335 patients with PD in the Parkinson's Progression Markers Initiative (PPMI) database, we investigated the longitudinal association of PD-associated polygenic load with changes in striatal dopaminergic activity as measured by 123I-N-3-fluoropropyl-2-β-carboxymethoxy-3β-(4-iodophenyl) nortropane (123I-FP-CIT) SPECT over 4 years. PD-associated polygenic load was estimated by calculating weighted genetic risk scores (GRS) using 1) all available 27 PD-risk single nucleotide polymorphisms (SNPs) in the PPMI database (GRS1) and 2) 23 SNPs with minor allele frequency >0.05 (GRS2).ResultsGRS1 and GRS2 were correlated with younger age at onset in patients with PD (GRS1, Spearman ρ = -0.128, p = 0.019; GRS2, Spearman ρ = -0.109, p = 0.047). Although GRS1 did not show an association with changes in striatal 123I-FP-CIT availability, GRS2 was associated with a slower decline of striatal dopaminergic activity (interactions with disease duration in linear mixed model; caudate nucleus, estimate = 0.399, SE = 0.165, p = 0.028; putamen, estimate = 0.396, SE = 0.137, p = 0.016).ConclusionsOur results suggest that genetic factors for PD risk may have heterogeneous effects on striatal dopaminergic degeneration, and some factors may be associated with a slower decline of dopaminergic activity. Composition of PD progression-specific GRS may be useful in predicting disease progression in patients.

Original languageEnglish
Pages (from-to)E665-E674
JournalNeurology
Volume93
Issue number7
DOIs
Publication statusPublished - 2019 Aug 13

Bibliographical note

Funding Information:
The present study is a secondary analysis of the PPMI study. This study was not supported by outside industries or government institutes. PPMI—a public–private partnership—is funded by the Michael J. Fox Foundation for Parkinson’s Research and funding partners, including AbbVie, Avid, Biogen, Bristol-Myers Squibb, Covance, GE Healthcare, Gen-entech, GlaxoSmithKline, Lundbeck, Eli Lilly, Merck, MesoScaleDiscovery, Pfizer, Piramal, Roche, Sanofi Gen-zyme, Servier, TEVA, and UCB.

Funding Information:
M. Lee reports no disclosures relevant to the manuscript. K. Pak is funded by the Basic Science Research Program through the National Research Foundation of Korea (NRF) (2017R1D1A1B03029352). J. Kim reports no disclosures relevant to the manuscript. Y. Kim received a grant from the NRF funded by the Korean government (NRF-2018R1D1A3B07047212). J. Yoon received a grant from the NRF funded by the Korean government (2017R1A2B4007831). J. Lee received a grant from the NRF funded by the Korean government (2017R1A2B4007831). C. Lyoo received a grant from the Basic Science Research Program through the NRF funded by the Ministry of Science, ICT & Future Planning (2017R1A2B2006694). H. Park received a grant from the Basic Science Research Program though the NRF funded by the Ministry of Education (2016R1D1A1B03932449). J.-H. Lee received a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare (HI18C0713). N.-Y. Jung received a grant from the Basic Science Research Program through the NRF funded by the Ministry of Education (2017R1D1A1B04028328), Republic of Korea. Go to Neurology.org/N for full disclosures.

All Science Journal Classification (ASJC) codes

  • Clinical Neurology

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